This invention relates to 1-(N-phenylaminoalkyl)piperazine derivatives substituted at position 2 of the phenyl ring, to pharmaceutical compositions containing them and to uses for such derivatives and compositions.
In mammals, micturition (urination) is a complex process that requires the integrated actions of the bladder, its internal and external sphincters, the musculature of the pelvic floor, and neurological control over these muscles at three levels (in the bladder wall or sphincter itself, in the autonomic centers of the spinal cord, and in the central nervous system at the level of the pontine micturition center (PMC) in the brainstem (pons) under the control of cerebral cortex) (De Groat, Neurobiology of Incontinence, (Ciba Foundation Symposium 151:27, 1990). Micturition results from contraction of the detrusor muscle, which consists of interlacing smooth muscle fibers under parasympathetic autonomic control from the sacral spinal cord. A simple voiding reflex is formed by sensory nerves for pain, temperature, and distension that run from the bladder to the sacral cord. However, sensory tracts from the bladder also reach the PMC, resulting in the generation of nerve impulses that normally suppress the sacral spinal reflex arc controlling bladder emptying. Thus, normal micturition is initiated by voluntary suppression of cortical inhibition of the reflex arc and by relaxation of the muscles of the pelvic floor and the external sphincter. Finally, the detrusor muscle contracts and voiding occurs.
Abnormalities of lower urinary tract function, e.g., dysuria, incontinence, and enuresis, are common in the general population. Dysuria includes urinary frequency, nocturia, and urgency, and may be caused by cystitis, prostatitis or benign prostatic hypertrophy (BPH) (which affects about 70% of elderly males), or by neurological disorders. Incontinence syndromes include stress incontinence, urgency incontinence, and overflow incontinence. Enuresis refers to the involuntary passage of urine at night or during sleep.
Prior to the work of the present inventors, treatment of neuromuscular dysfunction of the lower urinary tract has involved administration of compounds that act directly on the bladder muscles, such as flavoxate, a spasmolytic drug (Ruffman, J. Int.Med.Res. 16:317, 1988) also active on the PMC (Guarneri et al., Drugs of Today 30:91, 1994), or anticholinergic compounds such as oxybutynin (Andersson, Drugs 35:477, 1988). The use of xcex11-adrenergic receptor antagonists for the treatment of BPH is also common but is based on a different mechanism of action. (Lepor, Urology, 42:483, 1993).
However, treatments that involve direct inhibition of the pelvic musculature (including the detrusor muscle) may have unwanted side effects such as incomplete voiding or accommodation paralysis, tachycardia and dry mouth (Andersson, Drugs 35;477, 1988). Thus, it would be advantageous if compounds were available that act via the peripheral or central nervous system to, for example, affect the sacral spinal reflex arc and/or the PMC inhibition pathways in a manner that restores normal functioning of the micturition mechanism.
1-(N-phenyl-N-cyclohexylcarbonyl-2-aminoethyl)-4-(2-methoxyphenyl)piperazine (compound A) 
is described in GB 2 263110 A and is reported to be a 5-HT1A receptor antagonist. It is also disclosed that it can be used for the treatment of central nervous system disorders, for example as an anxiolytic agent in the treatment of anxiety.
The compounds of the present invention, described below, are structurally different from compound A because of the novel substituents present on the aniline ring at the 2 position. Other differences between the compounds of the present invention and those disclosed in GB 2 263110 A are the substitutions on the aromatic ring at position 4 of the piperazine ring. These structural variations are neither disclosed nor suggested by GB 2 263110 A, particularly with regard to compounds that can be used to improve urinary tract function. These structural variations result in compounds that are more potent than compound A in pharmacological tests predictive of activity on the lower urinary tract, in particular for activity against urinary incontinence.
Other compounds which have been found by the present inventors to be useful in the methods of the present invention, e.g., treatment of disorders of the urinary tract, are disclosed in U.S. Pat. No. 4,205,173; EP 711,757; DE patent 2,405,441; Chem. Pharm. Bull. 33:1823-1835 (1985), and J. Med. Chem. 7:721-725 (1964), all of which are incorporated by reference.
In one aspect the invention is directed to compounds of formula I: 
wherein
R is hydrogen
R1 is chosen from the group consisting of hydrogen and lower alkyl;
R2 is chosen from the group consisting of alkoxy, phenoxy, nitro, cyano, acyl, amino, acylamino, alkylsulphonylamino, alkoxycarbonyl, N-acylaminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminocarbonyl, aminocarbonyl, halo, trifluoromethyl or polyfluroalkoxy group,
n=1or 2;
B is chosen from the group consisting of optionally substituted aryl, optionally substituted bicyclic aryl group, optionally substituted 9-member bicyclic heteroaromatic containing one heteroatom, and an optionally substituted benzyl group,
with the proviso that if B is aryl and is substituted by an alkoxy group, the alkoxy group must be at the two position, and
if R1 is hydrogen and R2 is a nitro group and n=1, then B cannot be a phenyl, 2methoxyphenyl 4-chlorophenyl, 3 acetylphenyl, 3,4,5 trimethoxyphenyl, 2-chloro-4-methylphenyl or 2-pyridyl group; and
if R and R1 are hydrogen and B is optionally substituted phenyl, then R2 cannot be acyl, acylamino, alkoxycarbonyl, N-acylaminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminocarbonyl,
and enantiomers N-oxides hydrates and pharmaceutically acceptable salts thereof.
Preferred is when n=1. Further preferred is when B is optionally substituted phenyl. Further preferred is when B is indolyl.
Also preferred is when R1 is hydrogen; R2 is chosen from the group consisting of alkoxy, phenoxy, nitro, cyano, amino, halo, trifluoromethyl or polyfluroalkoxy; n=1; and B is substituted phenyl.
Also preferred is when R1 is hydrogen; R2 is chosen from the group consisting of alkoxy, phenoxy, nitro, cyano, amino, halo, trifluoromethyl or polyfluroalkoxy; n=1; and B is indolyl.
Also preferred is when R1 is hydrogen; R2 is chosen from the group consisting of alkoxy, nitro, halo, trifluoromethyl or polyfluroalkoxy; n=1, and B is substituted phenyl.
Also preferred is when R1 is hydrogen; R2 is chosen from the group consisting of alkoxy, nitro, halo, trifluoromethyl or polyfluroalkoxy; n=1; and B is substituted indolyl.
In another aspect, the invention is directed to compounds chosen from the group consisting of List I A:
1-[N-cyclohexylcarbonyl-N-(2-methanesulphonylaminophenyl)-2-aminoethyl]-4-(2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-methoxyphenyl)-2-aminoethyl]-4-(4-indolyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-benzyloxycarbonylpheny)-2-aminoethyl]-4-(2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(4-indolyl)piperazine;
1-[N-(2-nitrophenyl)-N-(2-pyrazinecarbonyl)-2-aminoethyl)]-4-(4-indolyl)piperazine,
1-[N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(2-methoxy-4-nitrophenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(2-methoxy-4-nitrophenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(4-amino-2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(4-acetylamino-2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(4-trifluoroacetylamino-2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-propoxycarbonylphenyl)-2-aminoethyl]-4-(2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-nitrophenyl)-2-aminoethyl]-4-[4-(N-acetyl-N-cyclohexylcarbonyl)amino-2-methoxyphenyl]piperazine;
1-[N-cyclohexylcarbonyl-N-(2-nitrophenyl)-2-aminoethyl]-4-[4-(bis-cyclohexylcarbonyl)amino-2-methoxyphenyl]piperazine,
1-[N-cyclohexylcarbonyl-N-(2-nitrophenyl)-2-aminoethyl]-4-[4-cyclohexanecarbonylamino-2-methoxyphenyl)piperazine,
1-[N-(2-nitrophenyl)-N-(2-pyrimidinecarbonyl)-2-aminoethyl)]-4-(2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-[2-(2,2,2-trifluoroethoxyphenyl)]-2-aminoethyl)]-4-(2-methoxy-4-nitrophenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-[2-(2,2,2-trifluoroethoxyphenyl)]-2-aminoethyl)]-4-(4-amino-2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-[2-(2,2,2-trifluoroethoxyphenyl)]-2-aminoethyl)]-4-(4-acetylamino-2-methoxyphenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-[2-(2,2,2-trifluoroethoxyphenyl)]-2-aminoethyl]-4-(4-indolyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-nitrophenyl)-2-aminoethyl)]-4-(4-acetylamino-2-methoxyphenyl)piperazine,
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(2-trifluoromethoxyphenyl)piperazine;
1-[N-(2-nitrophenyl)-N-(5-thiazolylcarbonyl)-2-aminoethyl)]-4-(2-methoxyphenyl)piperazine,
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(2-bromo-5-methoxybenzyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-iodophenyl)-2-aminoethyl 1-4-(4-indolyl)piperazine,
1-[N-(2-cyanophenyl)-N-cyclohexylcarbonyl-2-aminoethyl]-4-(2-trifluoromethoxyphenyl)piperazine;
1-[N-(2-cyanophenyl)-N-cyclohexylcarbonyl-2-aminoethyl]-4-(2-methoxy-4-nitrophenyl)piperazine;
1-[N-(2-cyanophenyl)-N-cyclohexylcarbonyl-2-aminoethyl]-4-(4-amino-2-methoxyphenyl)piperazine,
1-[N-(2-cyanophenyl)-N-cyclohexylcarbony-2-aminoethyl]-4-(4-acetylamino-2-methoxyphenyl)piperazine;
1-[N-(2-acetylphenyl)-N-cyclohexylcarbonyl-2-aminoethyl]-4-(2-methoxyphenyl)piperazine;
1-[N-(2-cyanophenyl)-N-cyclohexylcarbonyl-2-aminoethyl]-4-(4-indolyl)piperazine;
1-[N-(2-cyanophenyl)-N-cyclohexylcarbonyl-2-aminoethyl]-4-(2-bromo-5-methoxybenzyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl)-2-aminoethyl]-4-(1-cyclohexylcarbonyl-4-indolyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl )-2-aminoethyl ]-4-(4-amino-2-cyanophenyl)piperazine;
1-[N-cyclohexylcarbonyl-N-(2-trifluoromethoxyphenyl )-2-aminoethyl]-4-(2-cyanophenyl)piperazine;
1-[N-cyclohexylcarbony-N-(2-methanesulphonylaminophenyl)-2-aminoethyl] -4-(4-indolyl)piperazine; and
1-[N-cyclohexylcarbonyl-N-(2-methoxyphenyl)-2-aminoethyll-4-(1-cyclohexylcarbonyl-4-indolyl)piperazine,
and pharmaceutically acceptable salts thereof.
In yet another aspect, the invention is directed to compounds of formula IB 
wherein
R is a hydrogen atom, an alkylcarbonyl, a cycloalkylcarbonyl, a substituted cycloalkylcarbonyl or a monocyclic heteroarylcarbonyl group,
n=1 or 2;
R1 is a hydrogen atom or a lower alkyl group,
R2 is an alkoxy, phenoxy, nitro, cyano, acyl, amino, acylamino, alkylsulphonylamino, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminocarbonyl, N-acylaminocarbonyl, halo, trifluoromethyl or polyfluoroalkoxy group; and
B is a bicyclic heteroaromatic with the proviso that B is not a 9-member bicyclic heteroaromatic containing one heteroatom.
Preferred is when R is chosen from the group consisting of hydrogen and cycloalkylcarbonyl; R1 is hydrogen; R2 is chosen from the group consisting of alkoxy, phenoxy, nitro, cyano, acyl, amino, acylamino, alkylsulphonylamino, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminocarbonyl, N-acylaminocarbonyl, halo, trifluromethyl or polyfluroalkoxy group n=1, and B is a 10-member bicyclic heteroaromatic containing one heteroatom.
Further preferred is when n=1.
Further preferred is when B is a 10-member bicyclic heteroaromatic containing one heteroatom.
Further preferred is when B is an optionally substituted quinolyl.
The invention also includes the enantiomers, diastereomers, N-oxides, crystalline forms, hydrates and pharmaceutically acceptable salts of compounds of the formula 1 and 1B and the list 1A, as well as metabolites of these compounds having the same type of activity (hereafter sometimes referred to as xe2x80x9cactive metabolitesxe2x80x9d).
As used herein with reference to variable R, alkylcarbonyl radicals include C1-C6 alkylcarbonyl, cycloalkylcarbonyl includes cyclohexylcarbonyl, substituted cycloalkylcarbonyl includes cyclohexylcarbony substituted with alkyl or aryl groups and monocyclic heteroaryl radicals include monocyclic aromatic radicals of 5 to 7 ring atoms containing one or more hetero atoms (e.g., oxygen, nitrogen, and sulfur). Monocyclic heteroarylcarbonyl has the same definition as monocyclic heteroaryl, but also comprises a carbonyl group linked to a carbon atom of the ring.
As used herein with reference to variable B, a mono or bicyclic aryl radical means an aromatic radical having 6 to 12 carbon atoms (e.g., phenyl or naphthyl) which is substituted by one or more substitutents. Preferred substitutents for aryl radicals are lower alkyl, lower alkoxy (e.g., methoxy, ethoxy, propoxy, and butoxy), lower haloalkoxy (e.g., 2,2,2-trifluoroethoxy) halogen, amino, acylamino, alkylsulfonylamino, and (lower) alkylamino substituents.
As used with respect to variable B, monocyclic heteroaryl radical has the same meaning as for R, above, and bicyclic heteroaryl radical means a bicyclic aromatic radical containing one or more heteroatoms (e.g., nitrogen, oxygen, sulfur) and 9 to 12 ring atoms. Benzyl radicals, with respect to variable B, include phenylmethyl radicals which may be optionally substituted by one or more substituents. Preferred substituents for the benzyl radicals are alkyl, alkoxy, halogen, nitro, cyano, amido, amino, alkylamino, acylamino, alkylsulphonylamino or acyl substituents. Preferred substituents at B are optionally substituted monocyclic aryl and bicyclic heteroaryl. Most preferred substituents at B are alkoxyphenyl and mononitrogen-containing bicyclic heteroaryl.
Preferred substituents at R1 are hydrogen and methyl.
Preferred substituents at R2 are nitro, cyano, acyl, and aminocarbonyl. Most preferred at R2 is nitro. A preferred value for n is 1.
Preferred substituents for B are optionally substituted phenyl and indolyl.
The invention further provides pharmaceutical compositions comprising a compound of formula I, a specific compound from List 1A, or a compound of formula 1B, or an enantiomer, diastereomer, N-oxide, crystalline form, hydrate or pharmaceutically acceptable salt of the compound, in admixture with a pharmaceutically acceptable diluent or carrier.
In another aspect, the present invention is directed to methods for reducing the frequency of bladder contractions due to bladder distension by administering one or more selected compounds of Formula I, a specific compound from List 1A, or a compound of formula 1B, to a mammal (including a human) in need of such treatment, in an amount or amounts effective for the particular use.
In a further aspect, the present invention is directed to methods for treating disorders of the urinary tract in a subject in need of such treatment, comprising administering an effective amount of a compound of Formula 1, a specific compound from List 1A, or a compound of formula 1B, to ameliorate at least one of urinary urgency, increased urinary frequency, incontinence, urine leakage, enuresis, dysuria, urinary hesitancy, and difficulty in emptying bladder.
In yet another aspect, the invention is directed to methods for blocking 5-HT1A serotonergic receptors, and, by virtue of this inhibitory activity, to methods for the treatment of CNS disorders due to serotonergic dysfunction such as anxiety, depression, hypertension, sleep/wake cycle disorders, feeding behavior, sexual function and cognition disorders in mammals, particularly in humans, by delivering to the environment of the 5-HT1A serotonergic receptors, e.g., to the extracellular medium (or by administering to a mammal possessing such receptors) an effective amount of a compound of formula 1, list 1A, for formula 1B (hereinafter xe2x80x9ccompounds of the inventionxe2x80x9d).